Leukemia is a malignant disease of the bone marrow characterized by a block in differentiation, rapid proliferation and increased cell survival. Our long-term goal is to understand the role of PKC isozymes in leukemia cell physiology and translate this understanding into better diagnostic and therapeutic approaches. A significant clinical problem is resistance of many leukemias to commonly used chemotherapeutic drugs, such as paclitaxel (taxol). We recently found that atypical PKC confers resistance of human chronic myelogenous leukemia (CML) K562 cells to taxol-induced apoptosis. Preliminary data indicate that both the lambda/iota interacting protein (LIP), a specific activator of PKC, and the tyrosine kinase oncogene BCR-ABL are involved in resistance to apoptosis in K562 cells. Furthermore, the NF-kappaB transcription factor has been implicated as a downstream effector of PKC-mediated resistance to apoptosis. Based on these data, we hypothesize that PKC activity is critical for resistance to apoptosis and that both LIP and BCR-ABL are key regulators of PKC activity during apoptotic stress. We further hypothesize that PKC-mediated NF-kappaB activation is essential for resistance to taxol-induced apoptosis. Four specific aims are proposed to test these hypotheses. In Aim 1, we will determine whether PKC activity is required for resistance to taxol-induced apoptosis. In Aim 2, we will investigate the role of LIP in resistance to apoptosis and the mechanism by which LIP regulates PKC activity. In Aim 3, we will investigate the mechanism by which BCR-ABL regulates PKC activity. In Aim 4, we will determine whether NF-kappaB activation is a necessary downstream target of PKC in resistance to taxol-induced apoptosis and investigate how PKC activates NF-kappaB. Our results may uncover novel targets for therapeutic intervention in this disease and are likely to be relevant to the biology of many cancers.